Role of adjuvant chemoradiotherapy and chemotherapy in patients with resected gallbladder carcinoma: a multi-institutional analysis (KROG 19-04)

Objective: The effectiveness of adjuvant treatments for resected gallbladder carcinoma (GBC) has remained unclear due to lack of randomized controlled trials; thus, the aim of present study was to evaluate the role of adjuvant treatments, including chemoradiotherapy (CRT) and/or chemotherapy (CTx), in patients with resected GBC. Methods: A total of 733 GBC patients who received curative-intent surgical resection were identified in a multi-institutional database. Of 733 patients, 372 (50.8%) did not receive adjuvant treatment, whereas 215 (29.3%) and 146 (19.9%) received adjuvant CTx and CRT, respectively. The locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS) of the adjuvant treatment groups were compared according to tumor stage (stage II vs. stage III–IV). Results: In stage II disease (n = 381), the 5-year LRFS, RFS, and OS were not significantly different among the no-adjuvant therapy, CTx, and CRT groups, and positive resection margin, presence of perineural invasion, and Nx classification were consistently associated with worse LRFS, RFS, and OS in the multivariate analysis (P < 0.05). For stage III–IV (n = 352), the CRT group had significantly higher 5-year LRFS, RFS, and OS than the no-adjuvant therapy and CTx groups (67.8%, 45.2%, and 56.9%; 37.9%, 28.8%, and 35.4%; and 45.0%, 30.0%, and 45.7%, respectively) (P < 0.05). Conclusions: CRT has value as adjuvant treatment for resected GBC with stage III–IV disease. Further study is needed for stage II disease with high-risk features.


Introduction
Gallbladder carcinoma (GBC) is an aggressive tumor originating from the biliary tract and is known to have an unfavorable prognosis 1 . Surgical resection is known as the only curative treatment for localized GBC, but a relatively high recurrence rate after surgery remains a major concern 2-5 . Theoretically, adjuvant chemoradiotherapy (CRT) or chemotherapy (CTx) would be helpful to control the subclinical locoregional and systemic tumor burden after surgical resection; thus, the addition of adjuvant treatments might be a reasonable approach for resected GBC. However, although GBC is a malignancy of a subsite of the biliary tract and its natural course or etiology is distinctive from that of other subsites, most previous studies assessing the efficacy of adjuvant treatments in resected GBC included relatively small and heterogeneous populations, including GBC, intrahepatic and extrahepatic bile duct cancer and/or periampullary cancer 2,6-13 . The SWOG S0809 trial showed that adjuvant capecitabine and gemcitabine followed by CRT in resected GBC was feasible and effective, but it did not compare this treatment strategy with surgery alone 14 . Thus, the effectiveness of adjuvant treatments, including CRT or CTx, for resected GBC has remained unclear due to a lack of randomized controlled trials. Unfortunately, due to the rarity of GBC, conducting randomized controlled trials to evaluate the effectiveness of adjuvant treatments for resected GBC patients in the real world is difficult. For these reasons, the present study was designed to evaluate the role of adjuvant treatments, including CRT and/or CTx, in resected GBC compared with surgical resection alone using the multi-institutional database of the Korean Radiation Oncology Group (KROG) and to identify subgroups that are likely to benefit from adjuvant treatments by analyzing the clinicopathologic factors associated with recurrence and survival.

Patients
The data of GBC patients who underwent primary surgical resection with curative intent at any of the 12 KROG member institutions between October 2001 and October 2017 were reviewed. The inclusion criteria of the present study were as follows: histologically confirmed adenocarcinoma of the gallbladder; pathologic T2 or higher disease, assessed by the American Joint Committee on Cancer (AJCC) staging system (8 th edition); patients who underwent curative-intent surgical resection, defined as the eradication of the whole tumor(s) without gross residual disease; no distant metastasis; and no history of neoadjuvant treatment before surgery or previous or current malignancy. The clinicopathologic data of each patient, including age, gender, histologic findings, stage, serum carbohydrate antigen 19-9 (CA 19-9), surgical procedures, adjuvant treatments, sites and time of recurrence and survival, were collected. The collected data were managed by assigning case numbers to each participating institute and anonymizing them. Data analysis was performed centrally at the National Cancer Center, Republic of Korea, and all methods were performed in accordance with the relevant guidelines and regulations. This study was approved by the institutional review board of each participating institute and KROG (Approval No.  and complied with the Declaration of Helsinki and Good Clinical Practice guidelines. The requirement for written informed consent was waived due to the retrospective nature of the study.

Assessments and statistical analysis
Disease recurrence was confirmed pathologically and/or radiologically with evidence of an increase in size over time. Locoregional recurrence was defined as newly appearing or reappearing tumor(s) within the tumor bed and regional lymphatic area, including the porta hepatis, peripancreatic region, celiac region, origin of the superior mesenteric artery and para-aortic nodes, and distant recurrence was defined as newly appearing tumor(s) in distant organs or nonregional lymph nodes. Locoregional recurrence-free survival (LRFS) and recurrence-free survival (RFS), defined as the time from the date of surgical resection to the date of locoregional recurrence and any type of recurrence, respectively, and these were censored at the date of the last follow-up if the patients had no evidence of recurrence. Overall survival (OS) was defined as the time from the date of surgical resection to the date of death from any cause. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. In multivariate analysis, hazard ratios (HRs) were estimated using a Cox proportional hazards model. Statistical analyses were performed with STATA version 14.0 (StataCorp, College Station, TX, USA); all tests were 2-sided, and a P-value < 0.05 was considered statistically significant.
The baseline characteristics of the 3 adjuvant treatment groups (No-AT, CTx, and CRT) are compared in Table 1. For stage II patients, the No-AT group had significantly more older patients than the CTx group and had significantly fewer patients with positive resection margins than the CRT group (P < 0.05) ( Table 1). For stage III-IV patients, the No-AT group had significantly more older patients than the CTx and CRT groups and had significantly fewer patients with N1-N2 disease than the CTx and CRT groups (P < 0.05) ( Table 1). The other baseline characteristics were not significantly different among the 3 groups ( Table 1).
The median follow-up durations of all patients and living patients were 39.8 months [interquartile range (IQR), 21.1-75.0 months] and 58.9 months (IQR, 30.4-91.5 months), respectively. At the time of analysis, a total of 268 deaths were observed, 224 (83.6%) of which were from disease progression. Disease recurrence was observed in 300 (40.9%) patients, and the patterns of failure were locoregional recurrence in 94 (12.8%) patients, distant metastasis in 112 (15.3%) patients, and both locoregional and distant recurrences in 94 (12.8%) patients. The proportions of patients who experienced disease recurrence in stages II and III-IV were 21.8% and 61.6%, respectively (Figure 1). The patterns of failure in stage II showed no differences among the 3 adjuvant treatment groups (P > 0.05) ( Figure 1A). Regarding stage II disease, locoregional recurrence occurred in 12.4%, 18.3%, and 19.6% of the patients in the No-AT, CTx, and CRT groups, respectively, and distant metastasis occurred in 12.0%, 17.1%, and 19.6% ( Figure 1A). In stage III-IV patients, the rate of locoregional recurrence was significantly lower in the CRT group (25.7%) than in the No-AT and CTx groups (44.7% and 41.4%, respectively, P = 0.002) (Figure 1B), and the rates of distant metastasis were similar among the 3 groups (41.2%, 48.9%, and 39.0% in the No-AT, CTx, and CRT groups, respectively, P = 0.233). In contrast, the CTx group showed no significant difference in the patterns of failures compared with the No-AT group (P = 0.234).

Discussion
In evaluating the role of adjuvant treatments in resected GBC, a better understanding of the patterns of failures after curative resection could be a prerequisite, but it is still controversial 2,7,8,15-17 . Jarnagin et al. 2 compared the pattern of failure after curative resection between GBC (n = 97) and hilar cholangiocarcinoma (n = 80) and reported that recurrences in distant sites were more frequent in GBC than in hilar cholangiocarcinoma (85% vs. 41%, P < 0.001). Kim et al. 15 also reported that distant metastasis was a more dominant failure pattern (86%) than locoregional recurrence in resected GBC patients, but they addressed that the information regarding the recurrence pattern was incomplete. In contrast, Park et al. 7 reported that the most common failure site in resected GBC patients was aortocaval lymph nodes, i.e., 47.4% of all recurrences. Kim et al. 8 also reported that regional lymph nodes (27.7%) were the most frequent recurrence sites in resected GBC patients. Similarly, in the present study, locoregional    (Figure 1), and these findings suggested that the addition of CRT after curative resection could be a reasonable therapeutic option for resected GBC. In GBC, disease recurrence after curative resection frequently occurs, ranging from 31.9% to 66.3% in previous studies 2,7,8 and from 18.2% to 60.5% in ours, but the optimal adjuvant treatment modalities and their efficacy and indications remain unclear. Several studies evaluating the role of adjuvant treatments, including CRT and CTx, have been performed 3,9,12,15,[18][19][20][21][22] . Kim et al. 12 analyzed 151 patients with resected GBC, and adjuvant CRT was associated with significantly better LRFS and OS than CTx and No-AT in T2-3N1-2M0 stage disease, but not in T2-3N0M0. The multi-institutional study by Kim et al. 15 Table 2). These findings suggest that stage II resected GBC patients with these high-risk features could be potential candidates for adjuvant treatments, and further studies are warranted. The role of adjuvant CTx in resected GBC also remains unclear 6,18,24,25 . Subgroup analysis of 112 GBC patients in randomized phase III trials assessing the efficacy of adjuvant CTx using 5-FU and mitomycin C for pancreatobiliary cancer after surgical resection showed that adjuvant CTx improved OS compared with No-AT (5-year OS, 26% vs. 14.4%, P < 0.05), but most patients in this study had M1 disease (94% and 100% in the CTx and No-AT groups, respectively) 6 . Recently, a phase III randomized controlled trial assessing the clinical outcomes of adjuvant CTx with capecitabine compared with No-AT in 447 resected biliary tract cancer patients, including 79 (17.7%) GBC patients, showed that adjuvant CTx improved OS compared with No-AT in the per-protocol analysis (HR, 0.75; 95% CI, 0.58-0.97; P < 0.05), but the OS benefit of adjuvant CTx in the subgroup of GBC was not significant compared with No-AT (HR, 0.84; 95% CI, 0.43-1.63; P > 0.05) 25 . A meta-analysis regarding adjuvant treatments for resected bile duct cancer showed that the OS benefit from CTx or CRT was significantly greater than that from radiotherapy alone [odds ratio (OR), 0.39, 0.61, and 0.98, respectively, P = 0.02], and the greatest benefit from adjuvant CTx/CRT was in patients with positive lymph nodes (OR, 0.49) and microscopic residual disease (OR, 0.36) (P < 0.05) 24 . In contrast, an analysis of SEER data for GBC (n = 1,137) showed that the OS benefit from CRT  was greater than that from CTx and was prominent in T3-4 disease or positive lymph node disease 18 . Similarly, the present study showed that a statistically significant OS benefit in stage III-IV patients was derived from CRT compared with No-AT but not from CTx. However, in the present study, CRT significantly reduced the rates of locoregional recurrence compared with No-AT and CTx in stage III-IV patients (25.7%, 44.7%, and 41.4%, respectively, P = 0.002) but did not significantly reduce the rates of distant metastasis (39%, 41.2%, and 48.9%, respectively, P = 0.233). These findings suggest that recurrence at distant sites is still an important failure cause in stage III-IV patients even after CRT, and the addition of CTx to CRT may be meaningful because it effectively reduces distant metastasis. The present study had inherent limitations due to the use of retrospective data, heterogeneity of treatments in extent of surgical resection, details of radiotherapy and chemotherapeutic regimens, incompleteness of information on performance status and comorbidities of each patient, treatment-related toxicities, and so forth. Probable selection bias, the effect of these confounding factors, and treatmentrelated toxicities were not thoroughly addressed, but the present study included a relatively large study population (n = 733) using a multi-institutional database from KROG to minimize probable bias and the effects of confounding factors, and the heterogeneity of treatments in the present study reflected clinical practice in the real world. Furthermore, the present study included 112 (15.3%) patients who underwent cholecystectomy rather than radical cholecystectomy and 77 (10.5%) patients who did not undergo lymph node dissection, and these may lead to incorrect staging. Thus, in the present study, the extent of surgical resection and N classification were evaluated, and the prognostic significance for LRFS, RFS, and OS and Nx classification was consistently independent significant prognostic factor associated with LRFS, RFS, and OS in patients with stages II and III-IV (Tables 2 and 3). These findings suggest that the completeness of surgical resection is an important factor related with prognosis of GBC patients in the real world. In addition, although several studies evaluating the role of adjuvant treatments for resected GBC patients using SEER and/ or multi-institutional databases have been performed 18,20,21 , the present study compared the patient characteristics, patterns of failures, LRFS, RFS, and OS among adjuvant treatment groups according to stage and attempted to identify the subgroup most likely to benefit from adjuvant treatments, including CRT and/or CTx.

Conclusions
The present study showed that CRT significantly improved the LRFS, RFS, and OS of resected GBC patients with stage III-IV disease. In addition, the LRFS, RFS, and OS rates of stage II patients with high-risk features, such as positive resection margin, presence of perineural invasion, and Nx classification, were similar to those of stage III-IV patients receiving adjuvant CRT, and recurrence at distant sites was one of the main patterns of failures in stage III-IV, even after adjuvant CRT. Although the present study did not show the OS benefit of adjuvant CRT in stage II patients and the addition of CTx to CRT in stage III-IV patients, these findings suggest that further studies on CRT for stage II patients with high-risk features and the addition of CTx to CRT for stage III-IV patients are warranted.